Genome-wide association studies (GWAS) have recently identified a region of chromosome 9p21 as the most important source of heritable risk for cardiovascular disease. This locus is independent of traditional risk factors such as smoking, hypertension and hyperlipidemia, and the most predictive 9p21 variants account for more than 20% of an individual's lifetime risk for coronary artery disease. Despite being implicated in the leading cause of death in the Western world, the mechanism(s) by which these polymorphisms lead to vascular disease remain unclear. In this proposal, the investigators seek to elucidate the relationship between a leading candidate gene at the 9p21 risk locus, CDKN2B, and atherosclerosis. Specifically, they will query the role of this gene in a process known as efferocytosis, which is the phagocytic clearance of apoptotic debris. They will investigate how this process regulates the growth of the necrotic core in the developing atherosclerotic plaque and determine the downstream consequences of impaired efferocytosis. This proposal will bring together recognized experts from several fields, highly specialized translational reagents and unique mouse models with the objective of fully describing the vascular biology of CDKN2B. This application includes two specific aims which will: 1) Employ novel lineage tracing and cell-specific knockout models to determine how failed efferocytosis signaling regulates pro-atherosclerotic phenotype switching in the developing plaque; and 2) Test the translational utility of a novel high-affinity humanized antibody which may stimulate the removal of necrotic debris and induce atherosclerotic plaque regression. The objective of these studies is to 'reverse translate' the biology of the 9p21 locus and contribute to the field of cardiovascular genetics in the post-GWAS era. Discoveries made in the course of this proposal are intended to support the stated mission of the National Institutes of Health and provide contributions that will lead to the development of new translational therapies for patients with cardiovascular disease.